Obesity and obesity-related risk factors are associated with an increased risk of cardiovascular disease and events including carotid artery disease and stroke. The most common type of obesity in humans is diet-induced obesity. Inappropriate food-intake, particularly of a diet high in fat, is the primary cause of diet-induced obesity in humans. Although the incidence of obesity is increasing in the United States, very little is known regarding the effects of obesity on the vasculature and even less is known regarding mechanisms that limit or contribute to oxidative stress or endothelial dysfunction in blood vessels. Thus, the overall goal of this proposal is to examine potential mechanisms that contribute to oxidative stress and endothelial-dysfunction in a model of diet-induced obesity produced by a diet high in fat and one that recapitulates the development of obesity in humans. First, studies are proposed to examine the potential role of NAD(P)H oxidase as an important source of superoxide that contributes to vascular dysfunction produced by a high fat diet. Second, studies are proposed to determine whether IL-6, a potent pro-inflammatory cytokine, contributes to oxidative stress and vascular dysfunction produced by a high fat diet. Studies are designed to examine whether increases in IL-6 that occur with obesity are linked to enhanced NA(D)PH oxidase expression and/or activity. Conversely, studies are proposed to determine whether IL-10, a potent anti-inflammatory cytokine, limits oxidative stress and vascular dysfunction in response to a high fat diet. Studies are designed to examine whether the protective effect of IL-10 in limiting oxidative stress and endothelial dysfunction in obesity is mediated reductions in NAD(P)H oxidase activity and/or reduction in IL-6. Third, studies are proposed to examine whether deficiency of PARP-1, a downstream target of oxidative stress, limits the increase in oxidative stress and endothelial dysfunction in response to a high fat diet via reductions in NAD(P)H oxidase or IL-6 expression and/or increases in IL-10 or endothelial nitric oxide synthase. Our preliminary data support these hypotheses. Examination of mechanisms that contribute to or limit endothelial dysfunction in obesity are important because endothelial dysfunction has emerged as an independent clinical predictor of future cardiovascular disease and events. The results derived from the proposed studies should provide novel insight into mechanisms related to oxidative stress and endothelial dysfunction in response to diet-induced obesity.